HIV is primarily a sexually transmitted disease, resulting from exposure of the mucosa of uninfected people to infected genital secretions. We have studied HIV in semen in order to better understand sexual transmission, and to develop HIV prevention strategies. Work by our group and others has shown that antiretroviral treatment reduces the concentration of HIV in semen, and-accordingly-treated people are less contagious. However, even with treatment HIV RNA can be recovered from seminal plasma and HIV DNA from seminal cells. We would like to understand residual shedding of HIV so as to determine ongoing potential for HIV transmission, and to develop strategies to eliminate HIV from the male genital tract. In this Application we propose to better understand the pharmacology of ART in the male genital tract, to study virus shed in spite of treatment, and the conditions (factors) in semen that appear to permit HIV detection. We hope these results will determine the basis for residual shedding. HIV must be eliminated from the male genital tract to completely abrogate transmission, and to cure the infection.